52 consists of 52 issues, published weekly for one year, each issue detailing an actual week chronicling the events that took place during the missing year after the end of Infinite Crisis. The series covers much of the DC Universe, and several characters whose disparate stories interconnect. The story is directly followed by the weekly limited series Countdown to Final Crisis. It was the first weekly series published by DC Comics since the short-lived anthology Action Comics Weekly in 1988–1989.

The use of a weekly publication format is unusual in the North American comics industry, traditionally based upon a monthly publication. 52 and Batman Eternal (2014/2015) both hold the top position, of being the longest-published serialised weekly comic, published by a major North American publisher. The record was previously held by Action Comics Weekly. The story was originally conceived as being a chronicle of what happened in the "missing year" between the end of Infinite Crisis and the beginning of One Year Later. It would especially focus on how the world dealt with the disappearance of the "big three" heroes in the DCU, Superman, Batman, and Wonder Woman. As the series went on, it became more of a platform for which to set the stage for upcoming storylines in the DC Universe.

In the aftermath of Infinite Crisis, Superman, Batman, and Wonder Woman have temporarily retired their costumed identities, and the remaining heroes attend a memorial for Superboy in Metropolis. Time traveler Booster Gold attends the memorial, but when Superman, Batman, and Wonder Woman do not arrive as he expects, he suspects his robot sidekick Skeets is malfunctioning. After Skeets reports other incorrect historical data, Booster searches fellow time traveler Rip Hunter's desert bunker for answers, but finds it littered with enigmatic scrawled notes and photos of himself and Skeets surrounded by the words "his fault" with arrows pointing toward them. Booster's reputation is ruined by his unscrupulous attempts to maintain his corporate sponsorships, as well as the arrival of a mysterious new superhero named Supernova. Booster tries to regain the spotlight by containing an exploding nuclear submarine, but is seemingly killed in the attempt. Skeets uses Booster's ancestor Daniel Carter to regain access to Hunter's lab, where he sees the photos and arrows pointing at Skeets himself. Realizing that Hunter is aware of his plan, Skeets traps Carter in a time loop in the bunker and sets out to locate Hunter himself. He eventually corners Hunter and Supernova in the bottle-city of Kandor, where Supernova reveals himself to be Booster Gold, having faked his death with the help of Hunter to uncover Skeets' true intentions. Hunter and Booster attempt to trap Skeets in the Phantom Zone, but Skeets appears to consume the sub-dimension and pursues his two adversaries through time.

Ralph Dibny, the Elongated Man, is told that the gravestone of his dead wife Sue has been vandalized with an inverted version of Superman's "S" symbol, the Kryptonian symbol for resurrection. He confronts Cassandra Sandsmark, and she tells Dibny that she is in a cult which believes that Superboy can be resurrected, but they would like to try it first with Sue. Despite his initial consent, Dibny and his friends disrupt the ceremony, and the effigy of Sue crawls to Dibny, calling out to him as it burns; Dibny suffers a nervous breakdown as a result. Ralph seeks out the helmet of Doctor Fate, which promises to revive Sue if he makes certain sacrifices. With unwilling assistance of a demon he tied into knots using Gingold, Dibny journeys with the helmet through the afterlives of several cultures, where he is cautioned about the use of magic for personal gain. After several failed attempts to resurrect his wife, Dibny prepares a spell in Doctor Fate's home, the Tower of Nabu. Dibny puts the helmet on, points the gun at his temple, then shoots the helmet to reveal it is actually the sorcerer Felix Faust. Faust was posing as Nabu to give Dibny's soul to the demon Neron in exchange for his freedom. Neron kills Dibny, but realizes too late that Dibny's spell has trapped him and Faust inside a circle of binding that can only be undone by the person who originally created it. With Ralph's death, Neron and Faust are seemingly trapped together in the tower for all eternity. Ralph and Sue Dibny are reunited in death as ghost detectives.[4]

Lex Luthor announces the Everyman Project, a program designed to give ordinary people superpowers. John Henry Irons deactivates his niece Natasha's Steel armor after an argument about responsibility, then denies her pleas to be allowed to join the Everyman project. Following an encounter with Luthor, Irons' skin transforms into stainless steel, causing Natasha to accuse him of hypocrisy. Out of spite, she enrolls in the Everyman Project and becomes a member of Luthor's superhero team Infinity, Inc. Irons learns that Luthor can deactivate Everyman Project-given abilities and that they expire naturally after approximately six months. Luthor negates the powers of one of Natasha's teammates during a battle with fatal results, and Irons uses the death of her friend to convince Natasha to question Luthor's motives. After Luthor, angered by reports that he is incompatible with the treatment, deactivates the powers of the majority of the Everyman subjects on New Year's Eve, resulting in many of them falling from the sky to their deaths, Natasha works undercover to expose Luthor. Luthor eventually learns the reports were falsified by employees out of fear for what he might do with genuine superpowers, and gives himself the powers of Superman. He discovers Natasha's spying and beats her violently using his newfound powers. Irons and the Teen Titans attack Lexcorp and bring Luthor to justice with Natasha's help. Beast Boy offers Natasha, in her rebuilt Steel armor, membership in the Teen Titans, but she declines in favor of forming a new team with her uncle.

Animal Man, Starfire, and Adam Strange are marooned on an alien planet after the events of Infinite Crisis. They are pursued through space by agents of Lady Styx, whose forces are conquering and overrunning planets on a path of destruction toward Earth. They are rescued and joined by Lobo, who possesses the Emerald Eye of Ekron and claims he has found religion and turned his back on violence for the sake of his beloved Space Dolphins. Lady Styx hired Lobo to capture the heroes, but he instead delivers them to her so they can fight her. The heroes triumph, but not before encountering the Emerald Head of Ekron, a Green Lantern who fights alongside them to reobtain his eye (which is, in fact, a supercharged power ring). During the fight, Animal Man is injected with a toxin and dies. After Starfire and Strange lay his body to rest and leave, Animal Man awakens to find the aliens who gave him his powers standing over him, upgrading his powers to allow him to gain powers from any sentient being in the universe. Animal Man acquires the powers of Sun-Eaters, which he uses to return to Earth. He is pursued by Lady Styx's assassins, who are killed by Starfire just as they arrive at his home.

Black Adam, the superhuman leader of Kahndaq, forges a coalition with several other countries against the United States' superhuman supremacy under the Freedom of Power Treaty until Adrianna Tomaz, a former slave, shows Adam how he can use his abilities more peacefully to help his country. Adam convinces Captain Marvel to give Tomaz the power of Isis, and Adam and Isis free enslaved children across Africa. The Question, Renee Montoya, and Batwoman, meanwhile, discover that Intergang is preparing to invade Gotham City. Following a lead, the Question and Montoya fly to Kahndaq, where they prevent a suicide bombing at Black Adam and Isis' wedding, for which Adam awards them one of Kahndaq's highest honors. The four uncover Intergang, which is inducting children into a religion of crime based on its Crime Bible. Black Adam finds Isis' crippled brother Amon among the children and shares his power with him, and Amon is reborn as Osiris. Osiris befriends a seemingly timid anthropomorphic crocodile named Sobek, who joins Black Adam's Black Marvel Family. Adam and Isis inform the Freedom of Power Treaty member nations that Kahndaq is no longer interested in consolidating power or in executing superhumans.

Will Magnus, creator of the Metal Men, is abducted to Oolong Island, where Intergang and Chang Tzu are forcing kidnapped scientists to develop new weapons for them. Magnus' anti-depressants are confiscated and he is ordered to build a Plutonium Man robot, but Magnus also secretly rebuilds miniature versions of the Metal Men. The scientists activate three of their Four Horsemen of Apokolips, which target Black Adam. Suspicious of Black Adam, Amanda Waller destroys Osiris' reputation by maneuvering him into killing the Persuader and leaking footage of the incident to the media. Osiris retires from the public eye as a result, and acid rain ravages Kahndaq. Osiris, convinced that he is the cause of Kahndaq's new miseries, asks Captain Marvel to remove his powers, but he is confronted by Isis and Black Adam and returns to Kahndaq. Sobek tricks Osiris into turning back into Amon and devours him, revealing himself to be the fourth Horseman, Famine. The other Horsemen battle Black Adam and Isis. Isis is poisoned by Pestilence and dies while asking Adam to avenge her and Osiris' deaths.

Grief-stricken and enraged to the point of madness, Black Adam destroys the country of Bialya, base of the Four Horsemen, and murders the country's entire population before killing the last of the Horsemen. He attacks Oolong Island, but the scientists capture and imprison him. The Justice Society of America invade the island to arrest Adam and subdue the scientists, but Adam escapes and embarks on a week-long rampage across the globe, during which he kills several superhumans. During an enormous battle between many superhumans and Black Adam, Captain Marvel is unable to convince the Egyptian pantheon to remove Adam's powers, so he instead reverts him to Teth-Adam and changes Adam's magic word from "Shazam" to a new phrase. Teth-Adam goes missing in the resulting explosion and wanders the Earth powerlessly as he tries to guess the new magic word. He is seen wearing boots made from Sobek's skin.

The Question and Montoya train with Richard Dragon in Nanda Parbat, where Montoya learns that the Question is dying from lung cancer and wants her to replace him. After they discover a prophecy in the Crime Bible about Batwoman's death, the two join her fight against Intergang in Gotham City. When the Question's condition worsens, Montoya journeys back to Nanda Parbat in a failed attempt to save his life. Shortly after they leave Gotham, Intergang discovers Batwoman's identity and attempts to sacrifice her to fulfill the prophecy. Montoya, as the new Question, joins Nightwing and former Intergang member Kyle Abbot in trying to save Batwoman, but they are unable to prevent Mannheim from stabbing her with a ceremonial dagger. Batwoman fatally wounds Mannheim and survives. After she recovers, Montoya shines the restored Bat-Signal to call Batwoman back to work.

Skeets is revealed to be Mister Mind, who has been using Skeets' metallic body as a cocoon to metamorphose into a gigantic, monstrous form that feeds on time itself. Rip Hunter and Booster escape to the end of the Infinite Crisis, where they witness the secret creation of 52 identical parallel universes, which Mister Mind intends to consume. Daniel Carter reappears as the new Supernova and saves Hunter and Booster, restoring the Phantom Zone in the process. Mister Mind alters events in the 52 universes, creating new histories and a new status quo for each. Booster and Supernova trap Mister Mind in the remains of Skeets' shell and send him back in time to the beginning of the year, where he is captured by Dr. Sivana, trapped in a time loop for all eternity. Hunter, Booster, and Supernova agree to keep the restored multiverse's existence a secret, and Will Magnus rebuilds Skeets, using a copy he had made of the robot's memories.

The Science Squad are a group of fictional scientists and mad scientists in the DC Comics Universe. The group was created by writer Grant Morrison who stated, "I love writing cowardly, petulant, irascible supervillains much more than I enjoy writing truly evil ones, so this whole plot strand was a joy from beginning to end."[5] The members of the team are Veronica Cale, Doctor Death, Doctor Sivana, I.Q., Will Magnus, T.O. Morrow, Komrade Krabb, Dr. Tyme, and Robby Reed enemies Doctor Cyclops, Baron Bug, and Dr. Rigoro Mortis. They are commanded by Chang Tzu. They are featured prominently throughout the series, particularly in Week 46.

Dan DiDio included a hidden message in his "DC Nation" column in the back of Week 37. The message is spelled out using the first letter of every third word: "the secret of fifty-two is that the multiverse still exists".

Taking advantage of the popularity of the series, DC issued several series of comics based on the individual threads of 52 that began several months after 52 ended. Booster Gold (vol. 2) is an ongoing series that sees the eponymous hero and Rip Hunter travel through time to fix history as "the greatest superhero never known". The six-issue 52 Aftermath: The Four Horsemen mini-series covers the Four Horsemen's battle with Superman, Batman, and Wonder Woman. Black Adam: The Dark Age, another six-issue mini-series, follows Teth-Adam's quest to restore his powers and bring Isis back to life; it takes place between the end of 52 and Mary Marvel's corruption in Countdown.

Two strands of the 52 story were taken and put together with back-ups from the new Countdown story. Countdown to Adventure looks at the fate of space-travelers Adam Strange, Animal Man, and Starfire in their new roles after their journey over the course of eight issues, with a back-up story following Forerunner. Countdown to Mystery is another eight-issue series looking at the new Doctor Fate and a back-up story focusing on Eclipso.

These include:

Booster Gold vol. 2 – The further adventures of Booster Gold, Supernova, and Rip Hunter as they try to preserve the fractured timeline.

Black Adam: The Dark Age – In the aftermath of World War III, Black Adam tries to recoup his losses, for both his powers and personal life.

Infinity Inc. – Steel and the remaining members of Luthor's Everyman Project team together to form a new Infinity Inc.

In September 2006, DC Direct premiered a line of action figures based on 52. The first wave, featuring figures based on Batwoman, Isis, Booster Gold, Animal Man, and Supernova, was released in May 2007.[11]

Ace Books, under the imprint of the Berkley Publishing Group and published by the Penguin Group, released a novelization written by Greg Cox, with cover art by J. G. Jones and Alex Sinclair, and its design by George Brewer.

The novel primarily adapts the weekly limited series and the World War III tie-in miniseries. The novel deals with the plotlines of Montoya, the Question, Black Adam, Booster Gold, Skeets, and the 52 Earths, dropping the Luthor/Steel/Everyman Project, Ralph Dibny, and space plotlines completely and including only part of the "Science Squad" storyline, keeping in the evil geniuses and their work for Intergang but leaving out Will Magnus' ongoing plot; in his introduction, Cox explains that it was not possible to adapt all the plotlines of 52 within a novel of reasonable length. Outside of the loss of these various storylines from the book, events play out in an essentially identical manner, with most of the dialogue itself even lifted from the comics verbatim. There are some minor cosmetic changes along the way (for instance, on Week 3, Black Adam kills Intergang thug Rough House as opposed to Terra-Man), but in the final chapter, a lot of the specifics of Mister Mind's cross-time battle with Rip Hunter, Booster Gold, and Supernova are altered. The villain reveals himself in front of a gathered group of heroes in Metropolis, rather than to just Booster and Rip in the Fortress of Solitude; the rebirth of the multiverse is credited to Mister Mind's transformation, rather than the Crisis; and the weapon stolen from Steel by Booster during World War III is actually put to use against Mind, which it was not in the comic, and is the cause of his unexplained-in-the-comic shrinking.

In December 2007, GraphicAudio released the first half of a full cast audiobook adaptation based on the novel by Greg Cox. Like GraphicAudio's audiobook of Infinite Crisis, this spans two volumes (each 6 hours long) with 6 CDs and features a full cast, music, and sound effects. Volume 2 was released in February 2008.

In the CW series The Flash, the term '52' is often used as an Easter egg. For example, in the episode "Things You Can't Outrun", the Flash team opt to incarcerate criminal metahumans in "Area 52" at S.T.A.R. Labs.[12] In the second season, inter-dimensional breaches are made between Earth-One and Earth-Two, and 52 separate portals are located.[13]